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Purpose: Resolvin E1 (RvE1; RX-10001) belongs to a new class of endogenous immunoregulating mediators, originally identified as a metabolite of the omega-3 polyunsaturated fatty acid, eicosapentaenoic acid. Based on its proven efficacy in models of chronic inflammation, this study investigated the efficacy of resolvin E1 in a murine model of dry eye., Methods: C57/B6 mice, aged 6 to 8 weeks, were treated with systemic scopolamine and exposed to air draft and low humidity for 16 hours/day for 5 days and allocated to the following groups: unexposed controls, disease controls, treatment with vehicle or RvE1 delivered topically as its methyl ester prodrug, RX-10005, to enhance corneal surface penetration. Treatment was initiated at the time of desiccating stress induction. Treatment efficacy was assessed by corneal permeability using Oregon Green Dextran and by conjunctival goblet cell density using periodic acid-Schiff reagent., Results: RvE1 reduced the increase in corneal staining by 80% compared with untreated disease controls. Goblet cell density was reduced by 20% in disease controls but fully maintained in the group receiving RvE1., Conclusions: RvE1, delivered as its methyl ester prodrug, improved the outcome measures of corneal staining and goblet cell density in this murine model of dry eye, indicating the potential utility of endogenous resolvins and resolvin analogues in the treatment of dry eye.

Background: A significant correlation exists between disability and the volume of black holes (BHL VOL), defined as hypointense lesions on T1-weighted cranial magnetic resonance imaging. A consistent correlation has also been reported between urinary myelin basic protein-like material (MBPLM) and the transition toward secondary progression (SP) from relapsing-remitting (RR) multiple sclerosis (MS)., Objective: To improve the management of MS through a noninvasive and cost-effective test for monitoring disease activity or disease status., Design and Methods: From 662 patients with MS (86 with RR MS, 259 with SP MS without continued attacks, and 317 with SP MS with continued attacks), 24-hour urine samples were obtained at enrollment in the phase 3 Linomide (roquinimex) drug study. The urine specimens were analyzed for MBPLM and correlated with clinical features and findings on cranial magnetic resonance imaging., Results: Significant but weak correlations existed between urinary MBPLM and BHL VOL in all patients with MS (r = 0.114, P =.003; n = 662), patients with SP MS without attacks (r = 0.185, P =.003; n = 259), and all patients with SP MS (r = 0.122, P =.003; n = 576). No significant correlations were detected in the RR MS group or any of the disease groups or subgroups whose Expanded Disability Status Scale score was 5.0 or lower. In subgroup analysis, the most significant correlation was detected between urinary MBPLM after adjustment for creatinine and BHL VOL in patients with SP MS with an Expanded Disability Status Scale score of 5.5 or higher but without continued relapses (r = 0.417, P<.001; n = 138)., Conclusions: In patients with advanced SP MS, urinary MBPLM may possibly serve as an indicator of failed remission and axonal damage. Urinary MBPLM correlates with disease status in MS, especially the transition of RR MS to SP MS with advancing disability.

The synthetic immunomodulator Linomide, a quinoline-3-carboxamide, has a profound inhibitory influence in several experimental autoimmune diseases, including acute and chronic experimental allergic encephalomyelitis. In a double-blind trial, 31 patients with relapsing-remitting multiple sclerosis were randomized to oral doses of 2.5 mg Linomide or placebo once a day for six months. Fourteen patients receiving Linomide and 14 receiving placebo completed the trial, and the results were based on this population. The mean number of active (new and enlarged T2 weighted) lesions per monthly MRI scan was 1.37 in the patients receiving Linomide and 4.22 in the patients receiving placebo (p = 0.043). The percentage of scans with active MRI lesions was lower in the Linomide-treated group (p = 0.0064). When neurologic deficit was assessed by the Regional Functional Scoring System (RFSS), the Linomide group showed an improvement of 1% of the maximal RFSS range and the placebo group a deterioration of 0.2% (p = 0.14). There were three patients with relapses in the Linomide-treated group and six in the placebo group (p = 0.22). A slightly decreased proportion of natural killer cells in cerebrospinal fluid and peripheral blood was noted in the Linomide group. A severe adverse event of pleuropericarditis occurred in one of the Linomide-treated patients. The most frequent adverse event was musculoskeletal pain, of mild to severe degree, which tended to diminish after three months on Linomide therapy.

Parasympathetic and sympathetic nerve stimulation in vivo, individually and in combination, was used to study secretion and synthesis of amylase in the rat parotid gland. After 30 min with sympathetic nerve stimulation (3 Hz) a decrease in glandular amylase was seen, which corresponded approximately to the salivary output. On the other hand, after parasympathetic stimulation (10 Hz), chosen to obtain comparable amylase output, there was no decrease in glandular amylase, which points to synthesis during such activation. Experiments with incorporation of [3H]leucine, reflecting amylase synthesis, showed that both types of nerve stimulations increased such uptake in parotid protein. These results indicate that beside sympathetic activity, which is the main stimulus for granular amylase secretion, parasympathetic nerve impulses can evoke considerable amylase secretion because amylase synthesis is stimulated and amylase is rapidly available from a special, possibly non-granular pool. As expected from previous experiments an augmentation of amylase secretion was found, and the present experiments also indicated an augmentation at the level of synthesis when the two nerves were stimulated at the same time.

In anaesthetized rats the parotid saliva secreted during degeneration of the auriculo-temporal nerve contains amylase in fairly constant concentration, the amylase output varying with the secretory rate. The amount of amylase was not reduced by adrenoceptor blocking agents; it was increased by sympathectomy carried out one week in advance. A sympathetic degeneration secretion of amylase could also be demonstrated while the post-ganglionic sympathetic nerves were degenerating; a simultaneous parasympathetic degeneration secretion provided the salivary flow needed for the transport of the amylase.

Amylase secretion from dispersed lobules of the parotid gland of the rabbit was studied in response to isoprenaline (10(-8)-10(-5) M) and to carbachol (10(-8)-10(-5) M). The effects of each agent were investigated along and in combination at certain concentrations. Isoprenaline produced a dose-related amylase secretion with an average maximum of 688 units/100 mg, at 10(-5) M. The amylase secretion produced by submaximal concentrations of isoprenaline could be further increased by carbachol, already in low concentrations (10(-8)-10(-7) M), that were subthreshold for amylase secretion. This potentiating effect was seen not only as a larger secretion but also as a greater depletion of amylase from the tissue. In contrast to what is known from experiments in vivo, carbachol in a high concentration (10(-5) M), by activating muscarinic receptors only, released amylase to the same extent as that released by isoprenaline. This concentration of carbachol regularly decreased the amylase secretion evoked by isoprenaline, and may be regarded as unphysiologically high. The increase in isoprenaline evoked amylase secretion, brought about by carbachol in lower concentrations, may be due to an improved transport of amylase, because of secretion of fluid, but could also be caused by augmentation of the beta-adrenoceptor mediated effects.

In rabbits under urethane anaesthesia parotid secretion of fluid and amylase in response to electrical stimulation of the sympathetic and parasympathetic nerves was measured before and after injections of various agents acting on alpha-adrenoceptors. Amylase secretion in response to sympathetic nerve stimulation at 0.5 and 1 Hz was markedly reduced by clonidine, 0.5-30 micrograms/kg, in a dose related manner. The effect was not due to an altered responsiveness of the gland, since isoprenaline still caused a large release of amylase. Phenylephrine, 10 micrograms/kg, and prazosine, 300 micrograms/kg, had no effect on the sympathetically evoked amylase secretion. Yohimbine in a dose of 0.5 mg/kg increased the amylase output in response to sympathetic nerve stimulation at 0.5 Hz by 70%, while the response at 1 Hz, which is close to maximum for the gland, was not significantly increased. The fluid and amylase secretion produced by parasympathetic nerve stimulation at 1.5, 5.0 and 10 Hz remained unchanged after clonidine, 1.0-30 micrograms/kg, or yohimbine 0.5 mg/kg. In rabbits provided with chronic parotid fistulae fluid and amylase secretion were studied after injections of clonidine, 30 micrograms/kg, and yohimbine, 1 mg/kg. In the conscious animal clonidine reduced not only amylase but also fluid secretion, by around 50 and 30%, respectively, indicating an effect on the activity in both the sympathetic and parasympathetic secretory nerves. Yohimbine increased the output of amylase during feeding, seen as an increased mean output of amylase due to an increased concentration of amylase in the saliva, while fluid secretion remained unchanged. The various experiments suggest that amylase secretion in response to sympathetic activation may be influenced by prejunctional control of transmitter release via alpha-2-adrenoceptors, and that this control may be of physiological significance. Parasympathetically evoked secretion does not seem to be under the influence of a similar control.

After extirpation of the superior cervical ganglion in the rat a degeneration secretion of amylase occurs in an in vitro preparation of the parotid gland. It can be detected about 14 h after the sympathectomy, reaches a maximum after about 17 h and then slowly subsides. It is abolished by atenolol, but not by dihydroergotamine or atropine, nor by tetrodotoxin. From this it is concluded that the phenomenon is due to an action mainly on beta 1-adrenoceptors exerted by noradrenaline, which is released from the degenerating sympathetic nerves at the neuro-glandular junctions, independently of propagated nerve impulses.

Cat myocardium was used to investigate muscarinic receptor function in atria and ventricles. Carbachol and oxotremorine were used to determine agonist binding to the muscarinic receptors. It was found that carbachol was bound with almost the same characteristics in atria (KdH 1 microM; KdL 150 microM) as in ventricles (KdH 3 microM; KdL 150 microM). However, in the presence of guanylylimidodiphosphate Gpp(NH)p a difference was apparent so that the ventricular curve was shifted to a majority of low affinity sites whereas in atria two affinity sites remained even if the guanine nucleotide concentration was increased to 10 mM. Oxotremorine was bound with almost equal affinity in both atria and ventricles. The addition of Gpp(NH)p left all the receptors in the low affinity state irrespective of receptor localisation. The two agonists were also used to determine inhibition of adenylate cyclase activity. It was shown that the magnitude of adenylate cyclase inhibition was more pronounced in ventricles than in atria whether it was induced by oxotremorine or carbachol. When the effects of muscarinic agonists were determined on phosphatidylinositol metabolism it was shown that carbachol mediated a greater effect in atria than in ventricles. Almost no effect was seen with oxotremorine on phosphatidylinositol breakdown. Pirenzipine binding showed the presence of M1 receptors both in atria and ventricles. On the basis of diversity of muscarinic agonists on function and receptor occupancy it is suggested that heterogeneity exists for muscarinic receptors in both atria and ventricles.

H 160/51 is a calcium agonistic 1,4-dihydropyridine. Its optical isomers were now found to have opposing actions in the cat papillary muscle and rat portal vein. The inhibitory (+)-enantiomer had potencies of the same order as those of the stimulatory (-)-enantiomer. However the racemate and the (-)-enantiomer had approximately the same potencies and intrinsic activities. A model is presented to account for the fact that the effects of the inhibitory (+)-enantiomer can be concealed in the effects of the racemate of H 160/51.

The excitation of the chorda-tympani nerve caused a marked increase in the blood flow through the gland and in secretion of saliva; both phenomena had a threshold frequency of around 0.3 Hz and reached a maximum at around 20 Hz, where a 6-fold increase in the blood flow and a salivary secretion of at the most 300 microliters/min were seen. Sympathetic excitation severely retarded the blood flow, which almost ceased at frequencies as low as 3-5 Hz; mostly single shocks of sympathetic stimulation reduced the blood flow through the gland. An on-going parasympathetic activation did not alter the effects of sympathetic stimulation on the blood flow and the parasympathetically produced salivary secretion almost stopped. The experiments support previous results, which have suggested electrical excitation of the sympathetic trunk at or above 2 Hz to cause a vasoconstriction which adversely affects the fluid secretion in the rabbit salivary glands.

Saliva has been collected from conscious rabbits in response to feeding pellets and carrots and amylase concentrations and flow-rates were measured. Saliva was collected from a polythene tube permanently inserted into the main duct, which, in most cases, kept patent for about a fortnight without any obvious decrease in the secretory capacity of the glands. 2. With pellets the flow-rate varied between 50 and 1250 microliter./min, and the corresponding amylase concentration was relatively constant around 250 units/ml. When carrots were fed, the flow-rates were about threefold lower, but the amylase concentration was raised to a mean value around 1000 units/ml. In spite of the differences in flow-rates, the two kinds of food promoted the same maximum output of amylase, and the output for both kinds of food promoted the same maximum output of amylase, and the output for both kinds of food was found to increase with the flow-rate. 3. The amylase concentration in the saliva decreased after pre- or post-ganglionic sympathetic denervation, reducing the output of amylase by about 50%. However, the amylase concentration was further lowered by beta-adrenoceptor block, which decreased the output by an additional 25%, suggesting that circulating catecholamines contributed to the secretion of amylase. 4. The fluid secretion in response to pellets and carrots was mainly dependent on parasympathetic activity, and for both kinds of food the range of flow-rates was unaltered by sympathectomy or beta-adrenoceptor block. However, at flow-rates below 50 microliter./min, where 25% of all samples with carrots were obtained, sympathetic activity may have contributed significantly to the fluid secretion. 5. In experiments on anaesthetized rabbits, frequency-response curves for amylase and fluid secretion in response to parasympathetic and sympathetic activation were obtained. A comparison between these observations and those obtained in the conscious animals during feeding suggests a parasympathetic activity mainly between 1 and 5 Hz and a sympathetic around 1 Hz. 6. It is concluded that both parasympathetic and sympathetic secretory nerves are reflexly activated during feeding, and that the normal secretion during a meal is dependent on an interplay between the nerves. The results suggest that at least two different afferent nervous pathways are involved in the control of the secretory nerves.

Duct pressure and salivary flow were recorded in submaxillary glands of anaesthetized dogs, to study whether parasympathetic stimulation caused effects referable to activity in myoepithelial cells. At fairly low frequency of stimulation, e.g. 3 Hz, the pressure curve had two distinct components, with initial steep and a secondary gradual rise. It resembled that obtained on sympathetic stimulation, where the first phase is ascribed to myoepithelial contraction, the second phase to secretion. When parasympathetic stimulation ceased, there was first a steep fall, then a more gradual decline of the pressure. The steep fall was of the same magnitude as the steep rise; both increased with the frequency of stimulation. The size of the initial fall was fairly independent of the pressure level from which it started. Such a steep fall did not occur subsequent to parasympathetic stimulation if the myoepithelial cells were already in a state of strong contraction caused by sympathetic impulses or bradykinin. The phase of steep fall was inferred to be due mainly to relaxation of contracted myoepithelial cells, the following decline to back-flow of fluid into the gland. The salivary flow rate was highest at the beginning of a period of parasympathetic stimulation, particularly if the duct system was well filled and the saliva thin. It was concluded that myoepithelial contraction had initially expelled saliva. A brief period of parasympathetic stimulation while a slow basal secretion at constant rate was going on was found to accelerate this flow, and afterwards there was a transient deceleration of the flow. Acceleration was attributed partly to myoepithelial contraction, mainly to superimposed secretion; retardation to myoepithelial relaxation. The effect appeared independently of the way in which the basal flow was evoked, and the retardation resembled that seen after sympathetic stimulation or bradykinin.

1. In dogs under chloralose-urethane anaesthesia secretion from the submandibular gland was recorded with the outflow at gland level and at heights of up to 50 cm above the gland.2. With the outflow level increased, secretion elicited by sympathetic nerve stimulation was far better maintained before than after injection of the alpha-adrenoceptor blocking agent dihydroergotamine.3. When the outflow level was raised while no secretion occurred, fluid flowed into the gland. Part of this amount was returned on lowering the outflow to gland level. This volume was assumed to have been accommodated in the distended luminal system, whereas some fluid was obviously lost into the gland tissues.4. Both these fractions of the fluid flowing into the gland when the outflow level was high could be reduced by injecting the alpha-receptor agonist phenylephrine. Bradykinin, which like phenylephrine is known to contract salivary myoepithelial cells, had the same effect on the two inflow volumes.5. It is concluded that myoepithelial contraction reduced the distensibility of the luminal system and in addition supported the acini, thereby diminishing backflow into the glandular tissues and enabling the gland to discharge saliva against a high pressure.6. Morphologically it was found that in resting glands PAS-positive saliva was displaced from the ductal system when the outflow cannula was raised, but it was preserved in the lumina under similar conditions when the myoepithelial cells were being stimulated by phenylephrine or bradykinin.7. Although sympathetic secretion could be maintained against a head of pressure, so long as it was accompanied by myoepithelial contraction, the increased force caused by the secretion led to disruptive damage of striated ducts which are the first part of the luminal system not supported by myoepithelial cells.8. The morphological findings reinforce the belief that contraction of myoepithelial cells gives active support to the underlying parenchyma.

Sympathetic secretory responses from the parotid and the submaxillary glands of the rabbit were studied; sympathetic excitation occurred either alone or during a slow parasympathetic background secretion, imitating the resting secretion normally present. The fairly rapid sympathetically evoked flow of saliva from the parotid gland was, in the background secretion, further increased and obtained at low frequencies, which at sympathetic stimulation alone were subthreshold. The effects, which could be repeated with sympathomimetic drugs in a pilocarpine induced secretion, were abolished by alpha and beta-adrenoceptor blockade in combination. The submaxillary gland gave a very scanty secretion on sympathetic excitation, the effects being mediated via beta-adrenoceptors. The responses were not increased in a background secretion but the main effect of sympathetic activation was to retard the salivary flow. The retardation was attributed to vasoconstriction accompanying sympathetic excitation. Eliminating the vasoconstrictor responses, while retaining the sympathetic secretory effects, did not reveal any increase of the sympathetic salivary responses in the submaxillary gland.

1. In anaesthetized rabbits amylase secretion from the parotid gland was investigated. Secretion was evoked by sympathetic nerve stimulation, either alone or superimposed on a parasympathetic background secretion, imitating the resting secretion present in the waking animal.2. Sympathetic nerve stimulation at frequencies below 1 Hz was alone subthreshold for fluid secretion, but could greatly increase the amounts of amylase present in fluid secretion produced by parasympathetic nerve stimulation. The amylase output due to sympathetic nerve stimulation alone at 10 Hz did not exceed that seen in response to a stimulation at 1 Hz superimposed on parasympathetic activity.3. The amylase output in response to superimposed sympathetic stimulation was not influenced by the rate of fluid secretion, which was altered by stimulating the parasympathetic nerves at different frequencies.4. Sympathetically-evoked amylase secretion was abolished after beta(1)-block. The amylase secretion remaining on parasympathetic activation was sparse.5. It is concluded that secretion of amylase in response to sympathetic nerve stimulation requires the presence of a parasympathetic fluid secretion to be washed along the glandular ducts. Parasympathetic activity may also augment the sympathetic effect on amylase secretion.

Reflex secretion of amylase was studied in response to feeding pellets and carrots. Section of the ipsilateral glossopharyngeal nerve but not of the lingual nerve reduced the secretion of amylase with carrots but not with pellets. The fluid secretion was unaffected by the nerve sections. Larger volumes were secreted with pellets than with carrots, indicating that the hardness of the food, via chewing, is the main stimulus for fluid secretion. Sweet, salty, sour and bitter taste stimuli did not produce any fluid secretion in concentrations normally used for gustatory stimulation in rabbits. In a background flow of parasympathetically secreted saliva sweet stimuli regularly caused a large increase in the amylase output, salty stimuli usually had a small effect and sour and bitter stimuli seemed to have only exceptionally a small effect. Citric acid in a high concentration caused fluid secretion, at the most at a rate of about 50% of maximum; this saliva had a high content of amylase. The results support the view that during feeding the sympathetic secretory nerves can be activated via both taste stimulation and chewing, while the parasympathetic activity is mainly influenced by chewing.

The contribution by different autonomic receptors to the amylase secretion from the parotid gland of the anaesthetized rabbit was studied as the response to various parasympathomimetic and sympathomimetic drugs. Amylase secretion by infusions of pilocarpine and parasympathetic nerve stimulation was low, but regularly higher in response to pilocarpine than to parasympathetic nerve stimulation. These effects were reduced to the same level by beta-adrenoceptor block indicating the presence and for pilocarpine also the release of catecholamines, probably from the adrenals. Isoprenaline injections produced a high amylase secretion, that was blocked by atenolol, indicating that predominantly beta 1-adrenoceptors were activated. Phenylephrine was without amylase secretory effects. By accepting isoprenaline maximum as maximum for sympathetically produced amylase secretion, a theoretical frequency-response relationship for amylase secretion by sympathetic nerve stimulation could be calculated: ED50 was 0.9 Hz. The results indicate that under experimental conditions in vivo there are certain differences between the rat and the rabbit parotid glands in the autonomic control not only of fluid, but particularly of amylase secretion.

The secretory effect of sympathetic stimulation on the cat's submaxillary gland was augmented greatly when studied against a background of slow secretion evoked by parasympathetic stimulation at a low frequency and imitating the slow resting secretion normally present in the waking state. The sympathetic secretory threshold was markedly lowered, and even at low frequencies sympathetic stimulation caused a large, well-maintained response. After an alpha-adrenoceptor blocking drug sympathetic stimulation alone lost its secretory effect, but during resting secretion part of the accelerating effect was found to remain; this effect was elicited via beta-adrenoceptors. A marked secretory effect of sympathetic stimulation was also obtained during resting secretion in the parotid gland, where the sympathetic secretory effect is normally very small.

High concentrations of a novel peptide, neuropeptide Y, have been demonstrated in the guinea-pig and canine heart and in the latter, a particularly high concentration was found in the region of the coronary vasculature (126 +/- 31 pmol g-1). Intra-arterial infusion of neuropeptide Y for 30 s into the coronary artery of the intact, innervated dog heart resulted in a rapid and short-lasting reduction of blood flow from 38 +/- 4 to 31 +/- 3 ml min-1 (P less than 0.05) to resume control level, 39 +/- 5 ml min-1, within 5 min. These injections were unaccompanied by changes in heart rate and aortic pressure, while there was an associated small reduction in dP/dt, used as a measure for changes in contractility. In vitro studies using the isolated, paced papillary muscle from cat, guinea-pig and rat, and spontaneously beating right atria from the guinea-pig, demonstrated no effect of NPY on active tension or beating frequency. The results indicate that NPY has vasoconstrictor properties, but under the test circumstances to lack both positive and negative inotropic and chronotropic effects.

1. In dogs under chloralose-urethane anaesthesia the submaxillary duct was cannulated and connected either to an open outflow system, in which saliva displaced water, or to a closed pressure recording system.2. The secretory cells, which are supplied with beta-adrenoreceptors, were stimulated with isoprenaline, adrenaline or sympathetic nerve stimulation. Myoepithelial cells, supplied with alpha-receptors, were activated with phenylephrine, adrenaline or sympathetic stimulation, and also with bradykinin. To abolish alpha-receptor stimulating effects of adrenaline and sympathetic nerve stimulation, dihydroergotamine, phenoxybenzamine and phentolamine were used.3. When the secretory cells were activated alone, saliva flowed from the salivary duct, but the flow started late and only a moderately high pressure could be produced in the closed system. Saliva appeared much earlier in the duct when secretion was combined with myoepithelial contraction, and a much higher pressure could be built up in the duct system.4. It is concluded that rapid emptying of saliva in the mouth and a maintained flow at a high rate of the viscous saliva is promoted by contractions of the myoepithelial cells.